Stetter reactions of unsaturated 1-acyl-1H-pyrroles

Article abstract of DOI:10.1002/ejoc.201101151

α,β-Unsaturated 1-acyl-1H-pyrroles are employed as enabling units for the construction of 1,4-dicarbonyl systems using the organocatalytic Stetter reaction. The enhanced electrophilicity of the 1-acyl-1H-pyrrole unit allows for the catalytic construction of fused and non-fused pyranones from aliphatic aldehydes, is compatible with aromatic aldehydes, and also facilitates an intermolecular variant of the reaction involving both aromatic and aliphatic aldehydes.

Full text of DOI:10.1002/ejoc.201101151

FULL PAPER
DOI: 10.1002/ejoc.201101151
Stetter Reactions of Unsaturated 1-Acyl-1H-pyrroles
Christopher B. W. Phippen,[a] Anna M. Goldys,[a] and Christopher S. P. McErlean*[a]
Keywords: Synthetic methods / Organocatalysis / Nitrogen heterocycles / Carbenes / Cyclization / Umpolung
α,β-Unsaturated 1-acyl-1H-pyrroles are employed as en-
abling units for the construction of 1,4-dicarbonyl systems
using the organocatalytic Stetter reaction. The enhanced
electrophilicity of the 1-acyl-1H-pyrrole unit allows for the
catalytic construction of fused and non-fused pyranones from
aliphatic aldehydes, is compatible with aromatic aldehydes,
and also facilitates an intermolecular variant of the reaction
involving both aromatic and aliphatic aldehydes.
Introduction
Arduengo’s characterization of a stable N-heterocyclic
carbene (NHC) has led to an explosion of interest in these
previously overlooked molecules.[1] Whilst NHCs have been
widely adopted as a ligand-set for metal complex genera-
tion, their use in organocatalytic carbon–carbon bond con-
struction has been slower to gain momentum.[2] An early
example of an NHC-catalysed bond forming process was
disclosed by Stetter and co-workers.[3,4] Mimicking the ac-
tion of co-enzyme B1, Stetter employed an NHC for the
synthesis of 1,4-dicarbonyl systems through nucleophilic
addition of an aldehyde onto a Michael acceptor. The
mechanism of the Stetter reaction (Scheme 1) has recently
been verified and involves deprotonation of simple, often
commercially available, azolium salts to generate the cata-
lytically active NHC 2, which can undergo addition to an
aldehyde 3.[5–7] Proton transfer then effects a reversal of the
conventional reactivity of the aldehyde unit (umpolung)
and generates an acyl anion equivalent 5 (Breslow interme-
diate). These spectroscopically identifiable intermediates[5]
add to α,β-unsaturated carbonyl compounds to deliver 1,4-
dicarbonyl products. Despite the potential power of this
catalytic methodology, the Stetter reaction possesses some
limitations that have curtailed its application in target-ori-
ented synthesis.
Scheme 1. The mechanism of the Stetter reaction.
azolium salts, which require milder conditions to generate
the catalytically active NHC, and the use of more electro-
philic Michael acceptors to favour the Stetter pathway over
competing reaction pathways.[4,13,14] Rovis illustrated the
critical role of the Michael acceptor in Stetter cyclisations
by comparing the ring-closure of compounds 10–12 to give
tetrahydropyrans (Scheme 2).[15] The phenyl ketone 10 par-
ticipated in the reaction, but the more synthetically useful
ester 11 did not. Increasing the electrophilicity of the
Michael acceptor by employing the diester alkylidene 12
reinstated the Stetter reaction pathway.
Due to the pioneering work of Enders,[8,9] Rovis[10–12]
and others, the intramolecular Stetter reaction of aromatic
aldehydes to give six-membered rings has been developed
to a high degree. In contrast, the corresponding aliphatic
substrates are less frequently employed because the basicity
of the NHC can interfere with these enolisable substrates.
Solutions to this problem include the use of more acidic
In a bid to render the Stetter reaction more amenable to
target-oriented synthesis, we sought to employ a Michael
acceptor that incorporated the salient synthetic features re-
quired for widespread use. That is, an acceptor system that
was as electrophilic as a ketone, but that possessed the same
synthetic utility as an ester. Michael acceptors that fulfil
[a] School of Chemistry, The University of Sydney,
NSW 2006, Australia
Fax: +61-2-9351-3329
E-mail: christopher.mcerlean@sydney.edu.au
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101151 or from
the author.
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19 as a single geometric isomer in high yield over the two
steps.[20] The dithiane unit was cleaved to give the cycli-
sation precursor 20.
Scheme 2. Intramolecular pyranone syntheses reported by Rovis
and co-workers.
these criteria are the α,β-unsaturated 1-acylpyrroles. Unsat-
urated 1-acylpyrroles are known to be more electrophilic
than the corresponding esters. Shibasaki has calculated
their electrophilicity to be similar to that of the analogous
ketones.[16] The 1-acylpyrrole unit is also known to serve as
a surrogate for esters, acids, amides and aldehydes, making
it superior to the ester in terms of synthetic mallea-
bility.[17,18] Guided by these considerations, we set about ex-
ploring the Stetter reaction using 1-acylpyrrole Michael ac-
ceptors.
Scheme 4. Reagents and conditions: (a) HS(CH2)3SH, HCl, CHCl3,
81%; (b) benzaldehyde dimethyl acetal, PTSA, EtOAc; (c) 15,
NMM, CH2Cl2, 81% over two steps; (d) MeI, NaHCO3, CH3CN/
H2O, 44 %.
Results and Discussion
We elected to synthesise the required α,β-unsaturated 1-
acylpyrroles from the corresponding 1-propiolylpyrroles
through conjugate addition. Cognizant of the high level of
nucleophilicity of the 2- and 5-positions of the pyrrole ring
and of the enhanced electrophilicity of the Michael ac-
ceptor, we targeted the blocked 1-acyl-2,5-dimethylpyrroles.
To that end, 2,5-dimethyl-1-propiolylpyrrole (15) was gener-
ated through Paal–Knorr condensation of propiolamide
(14) and acetonylacetone under Dean–Stark conditions
(Scheme 3). The product 15 was a solid that could be stored
for extended periods at 4 °C without decomposition. Con-
jugate addition onto 15 provided substrates for the pro-
jected intramolecular Stetter reactions.
The number and identity of additional heteroatoms in
NHC frameworks is known to profoundly affect their
modes of reactivity. To effect the desired intramolecular
Stetter reaction we utilised carbenes generated from the thi-
azolium, imidazolium and triazolium salts shown in Fig-
ure 1. Experiments to uncover optimal reaction conditions
were performed as outlined in Table 1. In line with our pre-
vious results, thiazolium salts were found to give superior
yields of the fused pyranone 21, with the non-hygroscopic
salt 24 being optimal. Using 10 mol-% of thiazolium salt
24 and 10 mol-% triethylamine, the desired Stetter reaction
proceeded to give the bicyclic pyranone 21 as a single dia-
stereomer in 86% yield (Table 1, entry 13). The use of the
1-acylpyrrole unit allowed the loading of azolium salt to be
significantly reduced from 150 mol-% in our previous work
to just 10 mol-% in this work. In line with that earlier work,
NOE experiments confirmed the syn relationship of the hy-
drogen atoms adjacent to the ether linkage. This increased
Scheme 3. Reagents and conditions: (a) aq. NH3, 52%; (b) acetony-
lacetone, PTSA, benzene, Δ, 47%.
We have previously employed a Stetter reaction that was
super-stoichiometric in thiazolium salt to stereoselectively
generate fused pyranones using aliphatic aldehydes and α,β-
unsaturated esters.[19] To allow a direct comparison of the
effect of the 1-acylpyrrole unit, we studied the ring closure
of compound 20 (Scheme 4). To that end, 2-deoxy-d-ribose
(16) was treated with 1,3-propanedithiol under acidic condi-
tions to give the triol 17 in good yield. Triol 17 was treated
with benzaldehyde dimethyl acetal to give the six-membered
acetal 18 as a single diastereomer. Nucleophilic catalysed
conjugate addition of alcohol 18 onto 15 gave compound Figure 1. Azolium salts used for NHC generation.
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Stetter Reactions of Unsaturated 1-Acyl-1H-pyrroles
efficiency in accessing a fused six-membered ring from an tonation α to the ketone, or through an elimination–conju-
aliphatic aldehyde, vindicated our decision to employ an 1- gate addition of the ether oxygen.[23] Under the current re-
acylpyrrole unit.
action conditions it was not possible to distinguish between
these possibilities.
Table 1. Stetter cyclisations of compound 20.[a]
Aromatic aldehydes also participated in the 1-acylpyrrole
enabled intramolecular Stetter reaction. It has been well-
documented that the intramolecular Stetter reaction of aro-
matic aldehydes to give five-membered rings is the most fac-
ile version of the reaction and, for these non-enolisable sub-
strates, triazolium salt 22 provided optimal results. As
shown in Scheme 6, the oxygen-containing substrate 33 was
generated in short order by conjugate addition of salicyl-
aldehyde (32) onto 2,5-dimethyl-1-propiolylpyrrole (15).
The increased reactivity of this system allowed for a further
reduction in catalyst loading. Treatment of compound 33
with just 5 mol-% azolium salt 22 and 5 mol-% triethyl-
amine at room temperature gave the benzofuranone 34 in
good yield.
Entry
NHC
precursor
Base
Loading Solvent Temp.
Yield of
21 [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
22
22
22
22
22
22
25
26
23
23
24
24
24
DBU
DBU
DBU
TEA
TEA
TEA
DBU
DBU
TEA
TEA
Cs2CO3
TEA
TEA
0.2
1
THF
THF
toluene
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
r.t.
r.t.
n.r.
9
6
1
r.t.
1
r.t.
n.r.
10
31
12
13
n.r.
52
41
52
86
0.1
0.1
0.2
0.2
1
r.t.
reflux
reflux
reflux
r.t.
0.1
0.1
0.2
0.1
reflux
reflux
reflux
reflux
[a] Reactions performed overnight. [b] Isolated yield after
chromatography.
We next explored the generation of the corresponding
non-fused pyranones from aliphatic aldehydes. Due to the
increased rotational freedom associated with the linear pre-
cursor, these molecules have proven to be challenging sub-
strates to cyclise (see Scheme 5). In analogy to the foregoing
work, the known alcohol 27 underwent conjugate addition
onto 15 to give dithiane 28. Removal of the dithiane unit
revealed the cyclisation precursor 29. Treatment of 29 with
10 mol-% of thiazolium salt 24 and 10 mol-% triethylamine
gave the tetrahydropyranones 30 and 31 as a 2:1 mixture
of diastereomers in modest yield, with the cis-configured
pyranone predominating. Although there have been reports
of benzo-fused pyranones[9,21] and non-fused tetra-
hydrofuranones[12,22,23] being produced by intramolecular
Stetter reactions, this work represents the first generation
of a non-fused pyranone from an aliphatic aldehyde. Be-
cause the cyclisation precursor 29 was a single geometric
isomer, this result suggests a thermodynamic process. The
product distribution could result from deprotonation–pro-
Scheme 6. Reagents and conditions: (a) 15, NMM, CH2Cl2, 85%;
(b) 22 (5 mol-%), Et3N (5 mol-%), THF, 67%.
The corresponding aniline compound 36 underwent a
competing Friedländer quinoline synthesis under the reac-
tion conditions, so an electron-withdrawing group was ap-
pended to the nitrogen atom to attenuate the enamine reac-
tivity (Scheme 7). Conjugate addition of aniline 35 onto 15
gave 36 in good yield. Tosylation of 36 in the standard fash-
Scheme 5. Reagents and conditions: (a) 15, NMM, CH2Cl2, 69%;
(b) MeI, NaHCO3, CH3CN/H2O, 73%; (c) 24 (10 mol-%), Et3N
(10 mol-%), THF, Δ, 28%.
Scheme 7. Reagents and conditions: (a) 15, NMM, CH2Cl2, 95%;
(b) TsCl, Et3N, DMAP, 87%; (c) MeI, NaHCO3, CH3CN/H2O,
71%; (d) 22 (5 mol-%), Et3N (5 mol-%), THF, 81%.
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C. S. P. McErlean et al.
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ion, followed by deprotection, afforded the electronically
suitable cyclisation precursor 38, which underwent smooth
Stetter cyclisation to give the indanone 39 in good yield.
From a target-oriented perspective, convergent method-
ologies have proven to be invaluable for the synthesis of
complex molecular architectures.[24] In this regard, the
intermolecular Stetter reaction holds the appeal of uniting
two fragments to give a 1,4-dicarbonyl species without the
need for altering the oxidation states of the two carbonyl
units. Frustratingly, the NHC-catalysed intermolecular
Stetter reaction remains the most challenging version of this
carbon–carbon bond forming process.[25] Non-enolisable
aromatic and glyoxal aldehydes have been employed with
highly activated Michael acceptors including α,β-unsatu-
rated ketones, diester alkylidenes, nitroalkenes and keto-
amide alkylidenes to give the desired 1,4-dicarbonyl prod-
ucts in good yields.[26–30] At present, there are only a few
reports of enolisable aldehydes and unsaturated esters being
coupled in good yield using intermolecular Stetter reac-
tions.[31,32] We were highly gratified to observe that the 1-
acylpyrrole unit enabled the intermolecular Stetter reaction
to proceed smoothly (Scheme 8).
Conclusions
We have demonstrated that α,β-unsaturated 1-acylpyr-
roles are enabling units for the construction of 1,4-dicarb-
onyl systems using the NHC-catalysed Stetter reaction.
The enhanced electrophilicity of this unit allows for the
catalytic construction of fused and non-fused pyranones
from aliphatic aldehydes. The use of 1-acylpyrrole Michael
acceptors is compatible with aromatic aldehydes and also
facilitates the intermolecular variant of the reaction involv-
ing both aromatic and aliphatic aldehydes. Application of
the 1-acylpyrrole enabled Stetter reaction in a total synthe-
sis setting is underway within our laboratory.
Experimental Section
(2S,3R)-1-(1,3-Dithian-2-yl)butane-2,3,4-triol (17):[35] 2-Deoxy-d-
ribose (16; 1.5 g, 11 mmol) was dissolved in a mixture of chloro-
form (5.0 mL), and hydrochloric acid (6 m, 8.0 mL) and cooled to
0 °C. 1,3-Propanedithiol (1.5 mL, 25 mmol) was added and the
solution stirred overnight at room temperature. The precipitated
product was collected by filtration. The filtrate was extracted with
hot chloroform (100 mL) and the product, which crystallised from
the extract, was collected by filtration. The two batches of crystals
were combined and dried with phosphorus pentoxide under vac-
uum to give compound 17 as a beige solid (2.0 g, 81%); m.p.
125.3 °C (chloroform) (ref.[35] 124–125 °C). [α]D = –33.2 (c = 1.06,
MeOH); IR (neat): ν
= 3402, 3278, 2930, 2907, 1426, 1328,
˜
max
1092 cm–1. H NMR (300 MHz, MeOD): δ = 2.77 (dd, J = 11.0,
3.9 Hz, 1 H), 2.34–2.28 (m, 1 H), 2.22–2.17 (m, 1 H), 2.08–2.02 (m,
1 H), 1.95–1.89 (m, 1 H), 1.49–1.28 (m, 4 H), 0.64–0.55 (m, 2 H),
0.40–0.19 (m, 2 H) ppm. 13C (75 MHz, MeOD): δ = 76.3, 69.8,
64.6, 44.8, 40.3, 31.1, 30.5, 27.3 ppm. MS (ESI): m/z (%) = 247 (17)
1
[M
+ +
Na]+. HRMS (ESI): calcd. for C8H16O3S2Na [M
Na]+ 247.04331; found 247.04306
(2R,4S,5R)-2-Phenyl-4-[(1,3-dithian-2-yl)methyl]-1,3-dioxan-5-ol
(18):[36] To a solution of 17 (1.0 g, 4.5 mmol) in ethyl acetate
(9.0 mL) was added benzaldehyde dimethyl acetal (0.87 mL,
5.8 mmol) and p-toluenesulfonic acid (76 mg, 0.45 mmol), and the
reaction mixture was stirred overnight under a nitrogen atmo-
sphere. Triethylamine (0.22 mL, 1.6 mmol) was added and the sol-
vent was removed in vacuo. The residue was purified by column
chromatography over silica gel, eluting with 50% ethyl acetate in
hexanes, giving the impure acetal 18 as a colourless oil (1.3 g),
which was used directly in the subsequent reaction.
Scheme 8. Reagents and conditions: (a) 40, 24 (10 mol-%), Cs2CO3
(10 mol-%), THF, 42 (91%), 44 (63%), 46 (84%).
The use of 1-acryloyl-2,5-dimethylpyrrole (40)[33] as the
Michael acceptor enabled the straightforward intermo-
lecular Stetter reaction of both aliphatic and aromatic alde-
hydes. Ryu, Yang and co-workers have recently reported the
intermolecular Stetter reaction between acetaldehyde and
an unsaturated ketone as a biomimetic but pyruvate decar-
boxylase-independent, bond-forming process.[32,34] The 1-
acylpyrrole substrate 40 participated in an analogous pro-
cess to give 42 in excellent yield. The enhanced electrophi-
licity of the 1-acylpyrrole used in this work allowed the
amount of aldehyde employed to be greatly reduced. Only
1.1 equiv. of hexanal (43) and benzaldehyde (45) were
treated with 40 under the Stetter reaction conditions to give
44 and 46 in good yield. This enhanced reactivity with en-
olisable and non-enolisable aldehydes make the process
more amenable to target-oriented syntheses that require
complex aldehyde coupling partners.
Propiolamide (14):[37] Ethyl propiolate (2.0 mL, 20 mmol) was
added to aqueous ammonia (33% w/w; 50 mL) at 0 °C and the
reaction mixture was stirred for 1 h. The mixture was the poured
onto ethyl acetate (50 mL), the aqueous and organic portions were
separated, and the aqueous portion was further extracted with ethyl
acetate (3ϫ10 mL). The combined organic extracts were dried with
anhydrous Na2SO4 and the solvent and residual starting material
were removed in vacuo to give 14 as an off-white solid (0.70 g,
52%); m.p. 57 °C (ethyl acetate) (ref.[37] 57–58 °C). IR (neat): ν
˜
max
1H NMR
= 3317, 3122, 2790, 2106, 1659, 1371, 1131 cm–1
.
(300 MHz, CDCl3): δ = 6.32 (br., 1 H), 5.97 (br., 1 H), 2.86 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.0, 74.6, 68.1 ppm.
2,5-Dimethyl-1-propiolyl-1H-pyrrole (15): Propiolamide (14; 0.70 g,
10 mmol) was taken up in benzene (50 mL). p-Toluenesulfonic acid
(90 mg, 0.52 mmol) and 2,5-hexanedione (1.7 mL, 14 mmol) were
added and the reaction mixture was heated under reflux with a
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Stetter Reactions of Unsaturated 1-Acyl-1H-pyrroles
Dean–Stark apparatus overnight. The mixture was then cooled to
room temperature, sodium carbonate (0.30 g, 2.8 mmol) was added
and the mixture was stirred for 30 min. The solvent was removed
in vacuo and the residue was purified by column chromatography
over silica gel, eluting with 5% ethyl acetate in hexanes to give 15.
The silica gel was flushed with 10% methanol in dichloromethane,
the solvent was removed in vacuo, and the above procedure was
repeated. This gave the 15 as a pale-yellow solid (0.70 g, 47%); m.p.
sphere, was added triethylamine (1.1 μL, 7.9ϫ10–6 mol). Argon
was bubbled through the solution for approximately 5 min, then the
solution was stirred for a further 15 min. A solution of 20 (29 mg,
7.9ϫ10–5 mol) in THF (1.3 mL) was added by using a cannula and
argon was bubbled through the solution for approximately 5 min.
The reaction mixture was then heated to reflux temperature for
24 h. The solution was poured onto saturated aqueous ammonium
chloride (5 mL) and extracted with ethyl acetate (3ϫ5 mL). The
combined organic extracts were dried with anhydrous Na2SO4 and
the solvent was removed in vacuo. The residue was purified by col-
umn chromatography over silica gel, eluting with 10% ethyl acetate
in hexanes, to give 21 as a colourless solid (25 mg, 86%); m.p. 127–
128 °C (ethyl acetate/hexanes). [α]D = +5.50 (c = 1.51, CHCl3). IR
68.0 °C (ethyl acetate/hexanes). IR (neat): νmax = 3200, 2962, 2923,
˜
2099, 1551, 1361, 1323, 1058 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.85 (s, 2 H), 3.42 (s, 1 H), 2.49 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 151.2, 131.6, 112.5, 82.3, 78.0, 16.5 ppm.
MS (APCI): m/z (%) = 147 (100) [M]+, 120 (46).
(neat): ν
= 2962, 2926, 2877, 1711, 1372, 1261, 1106 cm–1. 1H
˜
max
(2R,4S,5R)-2-Phenyl-4-[(1,3-dithian-2-yl)methyl]-[(E)-5-(2,5-di-
methyl-1H-pyrrol-1-yl)-3-oxoprop-1-enoxy]-1,3-dioxane (19): To a
solution of the crude acetal 18 (1.3 g) in CH2Cl2 (23 mL) was added
2,5-dimethyl-1-propiolylpyrole (15; 0.77 g, 5.3 mmol) and N-meth-
ylmorpholine (0.74 mL, 6.7 mmol), and the reaction mixture was
stirred overnight at room temperature under a nitrogen atmo-
sphere. The solvent was then removed in vacuo and the residue was
purified by column chromatography over silica gel, eluting with 5%
ethyl acetate in hexanes followed by 10% ethyl acetate in hexanes,
NMR (300 MHz, CDCl3): δ = 7.49–7.37 (m, 5 H), 5.85 (s, 2 H),
5.60 (s, 1 H), 4.46–4.37 (m, 2 H), 4.13 (dddd, J = 12.0, 6.0, 6.0,
2.0 Hz, 1 H), 3.78 (dd, J = 18.0, 2.0 Hz, 1 H), 3.73 (dd, J = 18.0,
2.0 Hz, 1 H), 3.36 (d, J = 6.0 Hz, 2 H), 3.23 (dd, J = 16.0, 6.0 Hz,
1 H), 2.71 (dd, J = 16.0, 12.0 Hz, 1 H), 2.41 (s, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 204.6, 170.9, 137.2, 130.8, 129.4,
128.5, 126.3, 112.0, 101.5, 79.9, 75.8, 71.8, 69.2, 44.5, 40.9,
16.9 ppm. MS (ESI): m/z (%) = 761 (53) [2MNa]+, 538 (41), 295
(44), 130 (100). HRMS (ESI): calcd. for C21 H2 3NO5 Na
[M + Na]+ 392.14684; found 392.14709.
to give 19 as an off-white foam (1.7 g, 81% over two steps). [α]D
=
–17.3 (c = 1.60, CHCl ). IR (neat): ν = 2926, 1735, 1684, 1619,
˜
3
max
1369, 1245, 1194, 1140 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.58 (d, J = 12.0 Hz, 1 H), 7.52–7.38 (m, 5 H), 5.94 (d, J = 12.0 Hz,
1 H), 5.84 (s, 2 H), 5.55 (s, 1 H), 4.43 (dd, J = 10.8, 4.8 Hz, 1 H),
4.30 (dd, J = 10.2, 3.9 Hz, 1 H), 4.18–4.09 (m, 1 H), 3.99 (ddd, J
= 9.9, 9.9, 5.1 Hz, 1 H), 3.75 (dd, J = 10.5, 10.5 Hz, 1 H), 2.96–
2.83 (m, 4 H), 2.35 (s, 6 H), 2.32–2.22 (m, 1 H), 2.16–2.03 (m, 2
H), 1.98–1.84 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.3, 162.7, 137.1, 129.7, 129.3, 128.4, 126.3, 110.6, 104.2, 101.3,
76.0, 75.8, 68.4, 42.3, 37.6, 30.1, 29.6, 26.0, 15.5 ppm. MS (APCI):
m/z (%) = 460 (100) [M]+, 365 (32), 354 (38), 295 (46), 259 (36).
HRMS (ESI): calcd. for C24H29NO4S2Na [M + Na]+ 482.14302;
found 482.14306.
(E)-3-{[1-(Benzyloxy)-4-(1,3-dithian-2-yl)butan-2-yl]oxy}-1-(2,5-
dimethyl-1H-pyrrol-1-yl)prop-2-en-1-one (28): To a solution of
alcohol 27 (220 mg, 0.74 mmol) in CH2Cl2 (3 mL) was added 15
(130 mg, 0.89 mmol) and N-methylmorpholine (122 μL,
1.10 mmol) and the reaction mixture was stirred for 3 h at room
temperature under a nitrogen atmosphere. The solvent was then
removed in vacuo and the residue was purified by column
chromatography over silica gel, eluting with 10% ethyl acetate in
hexanes, to give 28 as a viscous yellow oil (226 mg, 69 %). IR
(CHCl ): νmax = 2931, 2908, 2862, 1681, 1620, 1365, 1195 cm–1. 1H
˜
3
NMR (300 MHz, CDCl3): δ = 7.68 (d, J = 12 Hz, 1 H), 7.35–7.29
(m, 5 H), 5.83 (d, J = 12 Hz, 1 H), 5.81 (s, 2 H), 4.54 (s, 2 H),
4.19–4.01 (m, 2 H), 3.58 (dd, J = 10.5, 3.6 Hz, 1 H), 3.53 (dd, J =
10.5, 6.3 Hz, 1 H), 2.88–2.83 (m, 4 H), 2.37–2.30 (m, 1 H), 2.33 (s,
6 H), 2.16–2.08 (m, 1 H), 1.93–1.81 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.5, 165.2, 137.6, 129.5, 128.6, 128.0,
127.7, 109.9, 102.8, 83.6, 73.6, 71.8, 47.0, 31.0, 30.4, 28.5, 25.9,
15.3 ppm. HRMS (ESI): calcd. for C24H31NO3S2Na [M + Na]+
468.16376; found 468.16386.
(2R,4S,5R)-2-Phenyl-4-(2-oxoethyl)-[(E)-5-(2,5-dimethyl-1H-pyrrol-
1-yl)-3-oxoprop-1-enoxy]-1,3-dioxane (20): Dithiane 19 (1.6 g,
3.5 mmol) was taken up in acetonitrile (34 mL) and water (6.8 mL).
Sodium hydrogen carbonate (3.0 g, 35 mmol) and methyl iodide
(2.2 mL, 35 mmol) were added and the mixture was stirred for 2 d
at room temperature. The reaction mixture was diluted with brine
(50 mL) and extracted with ethyl acetate (4ϫ60 mL). The com-
bined organic extracts were dried with anhydrous Na2SO4 and the
solvent was removed in vacuo. The residue was purified by column
chromatography over silica gel, eluting with 15% ethyl acetate in
hexanes, to give the title compound as a yellow oil (0.57 g, 44%).
(E)-5-(Benzyloxy)-4-{[3-(2,5-dimethyl-1H-pyrrol-1-yl)-3-oxoprop-
1-en-1-yl]oxy}pentanal (29): The dithiane 28 (200 mg, 0.450 mmol)
was taken up in acetonitrile (4 mL) and water (1 mL). Sodium hy-
drogen carbonate (188 mg, 2.25 mmol) and methyl iodide (140 μL,
2.25 mmol) were added and the solution was stirred overnight at
room temperature. The reaction mixture was then poured onto
water (25 mL) and extracted with ethyl acetate (3ϫ10 mL). The
combined organic extracts were dried with anhydrous Na2SO4 and
the solvent was removed in vacuo. The residue was purified by col-
umn chromatography over silica gel, eluting with 10% ethyl acetate
in hexanes, to give 29 as a viscous yellow oil (117 mg, 73%). IR
[α]D = –22.4 (c = 1.07, CHCl ). IR (neat): νmax = 3453, 2927, 1684,
˜
3
1619, 1369, 1231, 1196 cm–1. 1H NMR (300 MHz, CDCl3): δ =
9.85 (t, J = 1.8 Hz, 1 H), 7.56 (d, J = 11.7 Hz, 1 H), 7.46–7.37 (m,
5 H), 5.94 (d, J = 11.7 Hz, 1 H), 5.84 (s, 2 H), 5.59 (s, 1 H), 4.47
(dd, J = 11.0, 5.0 Hz, 1 H), 4.44–4.38 (m, 1 H), 4.10–4.02 (m, 1
H), 3.80 (dd, J = 10.5, 10.5 Hz, 1 H), 2.84 (dd, J = 7.2, 1.8 Hz, 2
H), 2.34 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 198.6,
167.4, 162.1, 136.6, 129.8, 129.5, 128.5, 126.2, 104.5, 101.6, 75.4,
74.6, 68.5, 53.6, 45.5, 15.6 ppm. MS (APCI): m/z (%) = 370 (49)
[M]+, 352 (37), 264 (28). HRMS (ESI): calcd. for C21H23NO5Na
[M + Na]+ 392.14684; found 392.14690.
(CHCl ): ν
= 2923, 2862, 1720, 1681, 1620, 1365, 1272, 1234,
˜
3
max
1195 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.78 (s, 1 H), 7.66 (d,
J = 12 Hz, 1 H), 7.38–7.29 (m, 5 H), 5.84 (d, J = 12 Hz, 1 H), 5.82
(s, 2 H), 4.55 (s, 2 H), 4.24–4.21 (m, 1 H), 3.60 (dd, J = 12.0,
6.0 Hz, 1 H), 3.54 (dd, J = 12.0, 6.0 Hz, 1 H), 2.60 (td, J = 6.0,
2.5 Hz, 2 H), 2.33 (s, 6 H), 2.11–1.90 (m, 2 H) ppm. 13C NMR
(2R,4aR,6S,8aS)-2-Phenyl-6-[2-(2,5-dimethyl-1H-pyrrol-1-yl)-2-
oxoethyl]tetrahydro-1,3-dioxino[4,5-e]pyran-7-one (21): To a solu-
tion of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (75 MHz, CDCl3): δ = 200.7, 168.3, 164.7, 137.5, 129.6, 128.6,
(2.1 mg, 7.9ϫ10–6 mol) in THF (0.70 mL) under an argon atmo-
128.0, 127.8, 110.1, 103.0, 82.7, 73.6, 71.6, 39.4, 23.8, 15.3 ppm.
Eur. J. Org. Chem. 2011, 6957–6964
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6961

C. S. P. McErlean et al.
FULL PAPER
HRMS (ESI): calcd. for C21H25NO4Na [M + Na]+ 378.16758;
found 378.16764.
= 17.1, 8.4 Hz, 1 H), 2.39 (s, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 200.7, 172.6, 170.0, 138.3, 130.8, 124.5, 122.4, 121.0,
113.7, 112.2, 81.2, 40.6, 17.0 ppm. MS (APCI): m/z (%) = 286 (100)
[M + H2O]+, 270 (45) [M + Na]+, 175 (32), 147(89). HRMS (ESI):
calcd. for C16H17NO4 [M + H2O]+ 287.10793; found 286.10738.
6-[(Benzyloxy)methyl]-2-[2-(2,5-dimethyl-1H-pyrrol-1-yl)-2-oxo-
ethyl]dihydro-2H-pyran-3(4H)-one (30 and 31): To a solution of 3-
benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (24; 7.5 mg,
2.8ϫ10–5 mol) in THF (2 mL) under an argon atmosphere, was
(E)-3-{[2-(1,3-Dithian-2-yl)phenyl]amino}-1-(2,5-dimethyl-1H-
added triethylamine (4.0 μL, 2.8ϫ10–5 mol). Argon was bubbled pyrrol-1-yl)prop-2-en-1-one (36): N-Methylmorpholine (64 mg,
through the solution for approximately 5 min and then the solution
was stirred for a further 15 min. A solution of 29 (100 mg,
2.81ϫ10–4 mol) in THF (3 mL) was added by using a cannula and
argon was bubbled through the solution for approximately 5 min.
The reaction mixture was then heated to reflux temperature over-
night. The solvent was removed in vacuo and the residue was puri-
fied by column chromatography over silica gel, eluting with 20%
ethyl acetate in hexanes, to give a mixture of 30 and 31 as a colour-
0.42 mmol) was added to a solution of 35 (89 mg, 0.42 mmol) and
15 (40 mg, 0.27 mmol) in dichloromethane (2 mL). The mixture
was stirred for 24 h, then the solvent was removed by evaporation.
The residues were subjected to flash column chromatography, elut-
ing with 2.5% ethyl acetate in hexanes, to give the title compound
as a colourless oil (91 mg, 95%). IR (neat): ν
= 2923, 1643,
˜
max
1591, 1458, 1367, 1262, 1065, 750 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 11.57 (br., 1 H), 7.55 (dd, J = 7.8, 1.2 Hz, 1 H), 7.47
(dd, J = 12.3, 8.1 Hz, 1 H), 7.34 (ddd, J = 8.4, 8.4, 1.2 Hz, 1 H),
7.20–7.12 (m, 2 H), 5.84 (s, 2 H), 5.43 (s, 1 H), 5.37 (d, J = 7.8 Hz,
1 H), 3.27 (m, 2 H), 3.03–2.96 (m, 2 H), 2.41 (s, 6 H), 2.27–2.18
(m, 1 H), 2.08–2.03 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.4, 146.7, 138.0, 129.6, 129.0, 128.7, 128.3, 124.6, 116.6, 109.5,
93.6, 47.7, 32.5, 25.2. 15.1 ppm. MS (ESI): m/z (%) = 381 (32)
[M + Na]+. HRMS (ESI): calcd. for C19H22N2OS2Na [M + Na]+
less oil (26.8 mg, 28%). IR (CHCl ): νmax = 2977, 2900, 1712, 1419,
˜
3
1280, 1365, 1095 cm–1. 1H NMR (300 MHz, CDCl3): δ (major iso-
mer) = 7.36–7.29 (m, 5 H), 5.83 (s, 2 H), 4.63–4.54 (m, 3 H), 4.18–
4.04 (m, 1 H), 3.58 (dd, J = 10.2, 5.7 Hz, 1 H), 3.51 (dd, J = 10.2,
4.5 Hz, 1 H), 3.37 (dd, J = 16.5, 5.7 Hz, 1 H), 3.15 (dd, J = 16.5,
5.4 Hz, 1 H), 2.75–2.50 (m, 2 H), 2.40 (s, 6 H), 2.22–1.96 (m, 2 H);
δ (minor isomer) = 7.36–7.29 (m, 5 H), 5.83 (s, 2 H), 4.74 (dd, J =
6.3, 4.5 Hz, 1 H), 4.63–4.54 (m, 2 H), 4.25–4.17 (m, 1 H), 3.68 (dd, 381.10712; found 381.10658.
J = 10.2, 5.4 Hz, 1 H), 3.59 (dd, J = 9.9, 4.5 Hz, 1 H), 3.31 (dd, J
(E)-3-{[2-(1,3-Dithian-2-yl)phenyl]tosylamino}-1-(2,5-dimethyl-
= 16.8, 4.2 Hz, 1 H), 3.16 (dd, J = 16.5, 6.3 Hz, 1 H), 2.75–2.50
(m, 2 H), 2.40 (s, 6 H), 2.22–1.96 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ (major isomer) = 207.0, 171.5, 138.0, 130.6,
130.5, 128.5, 127.8, 111.6, 79.4, 75.7, 73.6, 72.3, 40.0, 37.2, 28.4,
16.6; δ (minor isomer) = 210.5, 171.5, 138.0, 130.6, 130.5, 128.5,
127.8, 111.6, 79.4, 74.7, 71.9, 71.7, 40.4, 35.1, 23.8, 16.6 ppm.
HRMS (ESI): calcd. for C21H25NO4Na [M+ Na]+ 378.16758;
found 378.16768.
1H-pyrrol-1-yl)prop-2-en-1-one (37): Triethylamine (30 μL,
0.21 mmol), 4-(dimethylamino)pyridine (2 mg, 2.4ϫ10–5 mol) and
p-toluenesulfonyl chloride (31 mg, 0.16 mmol) were added to a
solution of 36 (55 mg, 0.15 mmol) in dichloromethane (3 mL). The
mixture was stirred for 4 h at room temperature before aqueous
sodium hydroxide (1 m, 10 mL) was added. The phases were sepa-
rated and the organic phase was washed with water (5 mL), dried
with Na2SO4 and the solvent was removed by evaporation. Flash
column chromatography, eluting with 10% ethyl acetate in hexanes,
gave 37 as a colourless solid (67 mg, 87%); m.p. 180–183 °C. IR
(E)-2-{[3-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-oxoprop-1-en-1-yl]oxy}-
benzaldehyde (33): N-Methylmorpholine (64 mg, 0.42 mmol) was
added to a solution of salicylaldehyde (42 mg, 0.42 mmol) and 15
(40 mg, 0.27 mmol) in dichloromethane (2 mL) and the mixture
was stirred for 24 h. The solvent was evaporated and the residue
was subjected to flash column chromatography, eluting with 15%
ethyl acetate in hexanes, to give the title compound (61 mg, 85%)
(neat): ν
= 2925, 1682, 1604, 1367, 1246, 1171, 930, 575 cm–1.
˜
max
1H NMR (300 MHz, CDCl3): δ = 8.43 (d, J = 13.2 Hz, 1 H), 7.87
(dd, J = 8.1, 1.2 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.44 (dd, J =
8.4, 6.9 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.21 (ddd, J = 7.8, 7.8,
1.2 Hz, 1 H), 6.49 (d, J = 8.1 Hz, 1 H), 5.71 (s, 2 H), 5.31 (s, 1 H),
5.09 (d, J = 13.2 Hz, 1 H), 3.06–2.81 (m, 4 H), 2.46 (s, 3 H), 2.12
(s, 6 H), 1.96–1.87 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
as a colourless oil. IR (neat): ν
= 1683, 1627, 1601, 1578, 1368,
˜
max
1139, 1059, 765 cm–1. H NMR (300 MHz, CDCl3): δ = 10.39 (s,
1
1 H), 7.98–7.93 (m, 2 H), 7.67 (ddd, J = 8.1, 7.5, 1.8 Hz, 1 H), 7.34 = 167.2, 145.6, 145.5, 139.9, 134.5, 132.8, 131.1, 131.1, 130.3, 129.8,
(dd, J = 7.5, 7.5 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 6.16 (d, J = 129.4, 129.4, 128.3, 110.3, 105.8, 46.2, 32.5, 32.2, 25.1, 21.8,
12.0 Hz, 1 H), 5.84 (s, 2 H), 2.34 (s, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 187.9, 166.8, 159.6, 157.4, 136.2, 129.8, 129.3, 126.7,
125.9, 118.5, 111.0, 108.1, 15.6 ppm. MS (ESI): m/z (%) = 292 (65)
[M + Na]+, 270 (34). HRMS (ESI): calcd. for C16H15NO3Na [M
+ Na]+ 292.09496; found 292.09441.
15.6 ppm. MS (ESI): m/z (%) = 535 (100) [M + Na]+. HRMS (ESI):
calcd. for. C26H28N2O3S3Na [M + Na]+ 535.11597; found
535.11543.
(E)-3-[(2-Formylphenyl)tosylamino]-1-(2,5-dimethyl-1H-pyrrol-1-
yl)prop-2-en-1-one (38): Dithiane 37 (60 mg, 0.15 mmol) was taken
up in a mixture of acetonitrile/water (4:1 v/v; 1 mL), sodium hydro-
gen carbonate (300 mg, 3.57 mmol) and methyl iodide (220 μL,
3.54 mmol) were added and the mixture was stirred for 24 h. The
mixture was diluted with ethyl acetate (10 mL) and water (10 mL),
the phases were separated and the organic phase was washed with
brine (10 mL) then dried with Na2SO4. The solvent was evaporated
and the residue was subjected to flash column chromatography
eluting with 10% ethyl acetate in hexanes to give the title com-
2-[2-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-oxoethyl]benzofuran-3(2H)-
one (34): Triazolium salt 22 (1.7 mg, 4.7ϫ10–6 mol) was dissolved
in THF (1 mL) and triethylamine (0.5 mg, 4.7 ϫ 10–6 mol) was
added. Argon was bubbled through the solution for 10 min. In a
separate flask, aldehyde (28 mg, 0.11 mmol) was dissolved in THF
(1 mL) and argon was bubbled through the solution for 10 min.
The aldehyde solution was added to the catalyst by using a cannula
and the mixture was stirred at room temperature for 24 h. The solu-
tion was evaporated and the residues were subjected to flash col-
umn chromatography, eluting with15% ethyl acetate in hexanes, to
pound as a colourless oil (35 mg, 71%). IR (neat): ν
= 2925,
˜
max
1693, 1594, 1367, 1246, 662 cm–1. H NMR (300 MHz, CDCl3): δ
1
give 34 as a colourless oil (19 mg, 67%). IR (neat): ν
= 2923, = 9.76 (s, 1 H), 8.54 (d, J = 13.5 Hz, 1 H), 8.07–8.04 (m, 1 H),
˜
max
1699, 1614, 1374, 1259, 757 cm–1. H NMR (300 MHz, CDCl3): δ
= 7.71–7.59 (m, 2 H), 7.13–7.08 (m, 2 H), 5.83 (s, 2 H), 5.11 (dd,
J = 8.4, 3.0 Hz, 1 H), 3.53 (dd, J = 17.1, 3.0 Hz, 1 H), 3.21 (dd, J
7.65–7.59 (m, 4 H), 7.34 (d, J = 8.1 Hz, 2 H), 6.91–6.88 (m, 1 H),
5.72 (s, 2 H), 5.02 (d, J = 13.5 Hz, 1 H), 2.47 (s, 3 H), 2.09 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 187.8, 166.7, 146.2,
1
6962
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6957–6964

Stetter Reactions of Unsaturated 1-Acyl-1H-pyrroles
145.6, 137.2, 135.3, 134.3, 133.9, 131.1, 130.7, 130.5, 129.7, 129.6,
111.6, 42.9, 37.2, 32.8, 31.5, 23.6, 22.5, 16.9, 14.0 ppm. HRMS
(ESI): calcd. for C15H23NO2Na [M + Na]+ 272.16210; found
128.2, 110.6, 105.1, 21.9, 15.3 ppm. MS (ESI): m/z (%) = 445 (100)
[M + Na]+. HRMS (ESI): calcd. for C23H22N2O4SNa [M + Na]+ 272.16257.
445.11980; found 445.11925.
1-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-phenylbutane-1,4-dione (46): 1-
Acryloyl-2,5-dimethylpyrrole 40 (50 mg, 0.33 mmol) was dissolved
in THF (1 mL) and argon was bubbled through the solution for
10 min. Benzaldehyde (36 μL, 0.36 mmol) was then added. In a
separate flask, caesium carbonate (10 mg, 33ϫ10–6 mol) and 3-
benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride 24 (9.0 mg,
33 ϫ 10–6 mol) were dissolved in THF and argon was bubbled
through the solution for 10 min. The aldehyde solution was added
to the catalyst by using a cannula and the mixture was stirred for
24 h. Water (5 mL) and ethyl acetate (10 mL) were added, the
phases were separated, the organic phase was dried with Na2SO4,
and the solvent was removed by evaporation. Flash column
chromatography eluting with 10% ethyl acetate in hexanes gave 46
2-[2-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-oxoethyl]-1-tosylindolin-3-one
(39): Triazolium salt 22 (0.43 mg, 1.1ϫ10–6 mol) and triethylamine
(0.11 mg, 1.1ϫ10–6 mol) were dissolved in THF (1 mL) and argon
was bubbled through the solution for 10 min. In a separate flask,
aldehyde 38 (10.0 mg, 23.7 ϫ 10–6 mol) was dissolved in THF
(1 mL) and argon was bubbled through the solution for 10 min.
The aldehyde solution was added to the catalyst solution by using
a cannula and the mixture was stirred for 24 h. The solvent was
evaporated and the residue was subjected to flash column
chromatography, eluting with 15% ethyl acetate in hexanes, to give
39 as a colourless oil (8.1 mg, 81%). IR (neat): ν
= 2928, 1723,
˜
max
1604, 1360, 1171, 663, 580 cm–1. 1H NMR (300 MHz, CDCl3): δ =
8.09 (d, J = 9.0 Hz, 1 H), 7.71–7.67 (m, 4 H), 7.26–7.22 (m, 3 H),
5.83 (s, 2 H), 4.31 (dd, J = 4.8, 3.9 Hz, 1 H), 3.85 (dd, J = 17.4,
4.8 Hz, 1 H), 3.71 (dd, J = 17.4, 3.9 Hz, 1 H), 2.38 (s, 6 H), 2.36
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.6, 170.2, 153.2,
145.4, 137.0, 133.0, 130.8, 130.2, 127.6, 125.2, 124.8, 124.6, 116.7,
112.0, 63.3, 41.2, 21.7, 16.9 ppm. MS (ESI): m/z (%) = 445 (100)
[M + Na]+. HRMS (ESI): calcd. for C23H22N2O4SNa [M + Na]+
421.12220; found 421.12165.
as an off-white solid (68 mg, 84%); m.p. 66–67 °C. IR (neat): ν
˜
max
= 2922, 1709, 1698, 1674, 1365, 1239, 1053, 778 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.02 (d, J = 7.5 Hz, 2 H), 7.60–7.45 (m, 3
H), 5.86 (s, 2 H), 3.47 (dd, J = 6.3, 6.0 Hz, 2 H), 3.23 (dd, J = 6.3,
6.0 Hz, 2 H), 2.45 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
198.1, 173.6, 136.6, 133.3, 130.7, 128.7, 128.1, 111.7, 33.7, 32.9,
17.0 ppm. HRMS (ESI): calcd. for C16H17NO2Na [M + Na]+
278.11515; found 278.11561.
Supporting Information (see footnote on the first page of this arti-
1-(2,5-Dimethyl-1H-pyrrol-1-yl)pentane-1,4-dione (42): 1-Acryloyl-
2,5-dimethylpyrrole 40 (66 mg, 0.44 mmol) was dissolved in THF
(1 mL) and argon was bubbled through the solution for 10 min.
Acetaldehyde (246 μL, 4.4 mmol) was then added. In a separate
flask, caesium carbonate (14 mg, 44ϫ10–6 mol) and 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride 24 (10.5 mg,
44 ϫ 10–6 mol) were dissolved in THF and argon was bubbled
through the solution for 10 min. The aldehyde solution was added
to the catalyst by using a cannula and the mixture was stirred for
24 h. Water (5 mL) and ethyl acetate (10 mL) were added, the
phases were separated, the organic phase was dried with Na2SO4
and the solvent was removed by evaporation. Flash column
chromatography eluting with 10% ethyl acetate in hexanes gave 42
1
cle): H and 13C NMR spectra of all reported compounds.
Acknowledgments
We thank Dr. C. J. Sumby (Adelaide) for the generous gift of imid-
azolium salts 25 and 26. C. B. W. P. and A. M. G. gratefully
acknowledge receipt of Australian Postgraduate Awards.
[1] A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. Chem. Soc.
1991, 113, 361.
[2] See the Supporting Information.
[3] H. Stetter, Angew. Chem. 1976, 88, 695; Angew. Chem. Int. Ed.
as a colourless solid (77 mg, 91%); m.p. 62–63 °C. IR (neat): ν
˜
max
Engl. 1976, 15, 639.
= 2928, 1704, 1363, 1263, 993, 777 cm–1 1H NMR (300 MHz,
.
[4] H. Stetter, H. Kuhlmann, Angew. Chem. 1974, 86, 589; Angew.
Chem. Int. Ed. Engl. 1974, 13, 539.
CDCl3): δ = 5.82 (s, 2 H), 3.04 (m, 1 H), 2.88 (m, 1 H), 2.41 (s, 6
H), 2.24 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 206.7,
173.4, 130.7, 111.7, 38.1, 32.8, 30.0, 17.0 ppm. MS (APCI): m/z (%)
= 194 (100) [M + H]+, 50 (50).
[5] A. Berkessel, S. Elfert, K. Etzenbach-Effers, J. H. Teles, Angew.
Chem. Int. Ed. 2011, 49, 7120.
[6] J. L. Moore, A. P. Silvestri, J. R. de Alaniz, D. A. DiRocco, T.
Rovis, Org. Lett. 2011, 13, 1742.
1-(2,5-Dimethyl-1H-pyrrol-1-yl)nonane-1,4-dione (44): 1-Acryloyl-
2,5-dimethylpyrrole 40 (50 mg, 0.33 mmol) was dissolved in THF
(1 mL) and argon was bubbled through the solution for 10 min.
Hexanal (43 μL, 0.36 mmol) was then added. In a separate flask,
caesium carbonate (10 mg, 33 ϫ 10–6 mol) and 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride 24 (9.0 mg,
33 ϫ 10–6 mol) were dissolved in THF and argon was bubbled
through the solution for 10 min. The aldehyde solution was added
to the catalyst by using a cannula and the mixture was stirred for
24 h. Water (5 mL) and ethyl acetate (10 mL) were added, the
phases were separated, the organic phase was dried with Na2SO4,
and the solvent was removed by evaporation. Flash column
chromatography eluting with 5% ethyl acetate in hexanes gave 44
[7] K. J. Hawkes, B. F. Yates, Eur. J. Org. Chem. 2008, 5563.
[8] D. Enders, T. Balensiefer, Acc. Chem. Res. 2004, 37, 534.
[9] D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107,
5606.
[10] T. Rovis, Chem. Lett. 2008, 37, 2.
[11] J. Read de Alaniz, T. Rovis, Synlett 2009, 1189.
[12] J. L. Moore, T. Rovis, in: Asymmetric Organocatalysis, vol. 291,
2010, pp. 77.
[13] T. Dröge, F. Glorius, Angew. Chem. Int. Ed. 2010, 49, 6940.
[14] S. Anjaiah, S. Chandrasekhar, R. Gree, Adv. Synth. Catal.
2004, 346, 1329.
[15] T. Rovis, M. S. Kerr, Synlett 2003, 1934.
[16] S. Matsunaga, H. Qin, M. Sugita, S. Okada, T. Kinoshita, N.
Yamagiwa, M. Shibasaki, Tetrahedron 2006, 62, 6630.
[17] S. D. Lee, M. A. Brook, T. H. Chan, Tetrahedron Lett. 1983,
24, 1569.
[18] D. A. Evans, G. Borg, K. A. Scheidt, Angew. Chem. 2002, 114,
3320; Angew. Chem. Int. Ed. 2002, 41, 3188.
[19] C. S. P. McErlean, A. C. Willis, Synlett 2009, 233.
[20] In line with previous reports and based on coupling constants,
we assigned this as the E isomer.
as an off-white solid (52 mg, 63%); m.p. 38.2–40 °C. IR (neat): ν
˜
max
= 2934, 1703, 1541, 1363, 1255, 1230 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 5.87 (s, 2 H), 3.05 (dd, J = 6.3, 6.0 Hz, 2 H), 2.85 (dd,
J = 6.6, 5.7 Hz, 2 H), 2.50 (dd, J = 7.5, 7.2 Hz, 2 H), 2.40 (s, 6 H),
1.66–1.56 (m, 2 H), 1.38–1.26 (m, 4 H), 0.89 (app. t, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.2, 173.6, 130.7,
Eur. J. Org. Chem. 2011, 6957–6964
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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